We propose to apply physical-chemical principles and biophysical techniques to the study of model systems of lipids important in the function and malfunction of the biliary system and liver and to correlate this information with actual physiological and pathological phenomena. The focus of this work will be on the physical chemistry and pathophysiology of bile. Bile is an aqueous solution containing four very different lipids, a bile salt mixture, lecithin, unesterified cholesterol, and conjugated bilirubin. As the normal solubility of these lipids in bile depends mainly upon the physical state of the lipids in solution, this work is aimed at elucidating the physical and chemical mechanisms underlying their solubility in bile and at determine the fine structure and characterization of the complexes involved both in model and native bile systems. Further primitive bile salts and bile salt analogues and other biodetergents will be studied to elucidate their gallstone dissolving potential. The major drugs which cause cholestasis inman are also lipids and are secreted both metabolized and unmetabolized into bile. We will study the physical- chemical properties of these drugs, both in model solution systems and at the air-water interface. Then their interaction with the normal lipids of bile individually and as their complex mixed micellar aggregates will be studied. The information derived from these model systems will then be correlated with actual physiological and pathologic phenomema: 1) the role of supersaturated bile in cholesterol and pigment gallstone formation, 2) the effects of bile salt analogues in primate bile formation and biliary lipid secretion, 3) the effects of bile and bile salt analogues on cholesterol gallstone dissolution and fragmentation in vitro, 4) the effects of cholestatic drugs in primate bile formation and biliary lipid secretion and 5) the physical state of bile and hepatic cholestatic deposits during cholestatic drug administration. A wide variety of biochemical, physiological, physical-chemical and biophysical techniques will be used. These are essential for developing the rationale proposed in this research.